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Combination of, or bispecific binding molecule to, immune checkpoint molecule antagonist and rank-l (nf- kb ligand) antagonist for cancer therapy or prophylaxis and uses therefore

A technology of immune checkpoints and antigen-binding molecules, applied in the direction of antibodies, drug combinations, immunoglobulins, etc.

Pending Publication Date: 2020-04-17
COUNCIL OF THE QUEENSLAND INST OF MEDICAL RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, a challenge in immunotherapy for solid and hematological malignancies is the discovery of new targets for patients who develop primary resistance to current immunotherapy combinations

Method used

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  • Combination of, or bispecific binding molecule to, immune checkpoint molecule antagonist and rank-l (nf- kb ligand) antagonist for cancer therapy or prophylaxis and uses therefore
  • Combination of, or bispecific binding molecule to, immune checkpoint molecule antagonist and rank-l (nf- kb ligand) antagonist for cancer therapy or prophylaxis and uses therefore
  • Combination of, or bispecific binding molecule to, immune checkpoint molecule antagonist and rank-l (nf- kb ligand) antagonist for cancer therapy or prophylaxis and uses therefore

Examples

Experimental program
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Effect test

Embodiment 1

[0972] Co-blockade of CTLA4 and RANKL suppresses lung metastasis depending on NK cells and IFN-γ

[0973] In mice bearing experimental B16F10 melanoma lung metastases, hamster anti-CTLA4 (UC10-4F10) and rat anti-RANKL (IK22 / 5) Wild-type (WT) mice treated with MAb combination showed superior tolerance to metastasis (Fig. 1A). CD8 depletion + The mechanism of action of anti-CTLA4 and anti-RANKL combination therapy was confirmed in wild-type mice with NK cells or mice lacking perforin or IFNγ. like figure 1 As shown in B, the efficacy of this combination depends on NK cells rather than CD8 + T cells are present, while IFNγ is critical and perforin plays a role to a lesser extent ( figure 1 C). A similar dependence on NK cells was demonstrated for effective control of experimental lung metastases from prostate cancer RM-1 after treatment with the same anti-CTLA4 and anti-RANKL combination therapy (Fig. 1D).

Embodiment 2

[0975] Optimal synergy of anti-RANKL and CTLA4 antibody IgG2A isoforms

[0976] Given that the immunoglobulin constant region against CTLA4 has been reported to affect antitumor activity (Selby et al., 2013, Cancer Immunol. Res., 1(1):32-42)), the inventors next evaluated different anti-CTLA4 How antibody isotypes synergize with anti-RANKL to suppress experimental B16F10 lung metastases ( figure 2 ). 9D9 is an anti-CTLA4 clone that has produced multiple isotypes, including mouse IgG1, IgG2a, and IgG2b; while another isotype (IgG1-D265A) contains a mutation that abolishes binding to all Fcγ receptors (FcγRs) (Selby et al., 2013 supra). like figure 2 A shows that the anti-CTLA4 IgG2a isotype alone (closed circles) has a greater inhibitory effect on lung metastasis compared to the anti-CTLA4 hamster clone (inverted closed triangles), and the increase with the increase of This inhibition was further enhanced with the addition of anti-RANKL. Similarly, significant inhibition...

Embodiment 3

[0979] Anti-RANKL and anti-CTLA4 inhibit the growth of subcutaneous B16F10 melanoma

[0980] Next, the efficacy of dual blockade of RANKL and CTLA4 was assessed in mice bearing subcutaneous B16F10 melanoma, which is generally poorly immunogenic ( image 3 ). Similar to the lung metastases model, it was again confirmed that the combination treatment inhibited growth better than monotherapy, although the combined effect with the anti-CTLA4 hamster isoform was not significant.

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Abstract

Disclosed are agents for treating or preventing cancers. More particularly, the present invention discloses the therapeutic combinations comprising antagonists of receptor of NF-KB (RANK) ligand and immune checkpoint molecules in methods and compositions for treating or inhibiting the development, progression or recurrence of cancers, including metastatic cancers.

Description

[0001] title [0002] "Agents for the treatment or prevention of cancer and uses thereof" technical field [0003] This application claims priority to Australian Provisional Application No. 2017902125, entitled "Agents for the treatment or prevention of cancer and uses thereof", filed 5 June 2017, the contents of which are incorporated herein by reference in their entirety. [0004] The present invention generally relates to agents for the treatment or prevention of cancer. More specifically, the present invention relates to receptors and immune checkpoint molecules comprising NF-κB (RANK) ligands in methods and compositions for treating or inhibiting the development, progression or recurrence of cancer, including metastatic cancer. Therapeutic Combinations of Antagonists. Background technique [0005] The National Cancer Institute estimates that in the United States alone, one in three people will be diagnosed with cancer during their lifetime. Additionally, approximatel...

Claims

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Application Information

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IPC IPC(8): A61K39/395C07K16/46A61P35/00A61P37/00
CPCA61P35/00A61P37/00C07K16/2818C07K16/2875A61K2039/507C07K16/468C07K2317/31C07K2317/55C07K2317/76Y02A50/30A61P35/04C07K16/2878
Inventor B·杜加尔M·邓E·艾伦M·史密斯
Owner COUNCIL OF THE QUEENSLAND INST OF MEDICAL RES
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